2020–2021 BCSC Basic and Clinical Science Course™
9 Uveitis and Ocular Inflammation
Chapter 1: Basic Concepts in Immunology: Effector Cells and the Innate Immune Response
Mediator Systems That Amplify Immune Responses
Although innate or adaptive effector responses may directly induce inflammation, in most cases this process must be amplified to produce overt clinical manifestations. Molecules generated within the host that induce and amplify inflammation are termed inflammatory mediators, and mediator systems include several categories of these molecules (Table 1-2). Most act on target cells through receptor-mediated processes, although some act in enzymatic cascades that interact in a complex fashion.
Plasma-Derived Enzyme Systems
Complement is an important inflammatory mediator in the eye. Complement components account for approximately 5% of plasma protein and comprise more than 30 different proteins. Complement is activated by 1 of 3 pathways, and this activation generates products that contribute to the inflammatory process (Fig 1-3):
Classic pathway activation occurs upon fixation of complement C1 by antigen–antibody (immune) complexes formed by IgM, IgG1, or IgG3. This pathway results in a connection between innate and adaptive immunity.
Alternative pathway activation occurs continuously but is restricted by host complement regulatory components.
The mannose-binding lectin pathway is activated by certain carbohydrate moieties on the cell wall of microorganisms.
Complement serves the following 4 basic functions during inflammation:
coats antigenic or pathogenic surfaces with C3b to enhance phagocytosis (opsonization)
promotes lysis of cell membranes through pore formation by the membrane attack complex (MAC)
recruits neutrophils and induces inflammation through generation of the anaphylatoxins C3a and C5a
modulates antigen-specific immune responses through complement activation products, such as iC3b and MACs
Table 1-2 Mediator Systems That Amplify Innate and Adaptive Immune Responses
Figure 1-3 Overview of the essential intermediates of the complement pathway. C3a, C3b, C5a, and C5b are complement split products. C5b combines with intact C6, C7, C8, and C9 from the serum.
Anaphylatoxin effects include chemotaxis, changes in cell adhesiveness, and degranulation and release of mediators from mast cells and platelets. C5a stimulates oxidative metabolism and the production and release of toxic oxygen radicals from leukocytes, as well as the extracellular discharge of leukocyte granule contents.
Fibrin and other plasma factors
Fibrin is the final deposition product of the coagulation pathway. Its deposition during inflammation promotes hemostasis, fibrosis, angiogenesis, and leukocyte adhesion. Fibrin is released from its circulating zymogen precursor, fibrinogen,upon cleavage by thrombin. In situ polymerization of smaller units gives rise to the characteristic fibrin plugs or clots. Fibrin dissolution is mediated by plasmin, which is activated from its zymogen precursor, plasminogen, by plasminogen activators such as tissue plasminogen activator. Thrombin, which is derived principally from platelet granules, is released after any vascular injury that causes platelet aggregation and release. Fibrin may be observed in severe anterior uveitis (the “plasmoid aqueous”), and it contributes to complications such as synechiae, cyclitic membranes, and tractional retinal detachment.
Histamine is present in the granules of mast cells and basophils and is actively secreted after exposure to a wide range of stimuli. Histamine acts by binding to 1 of at least 3 known types of receptors that are differentially present on target cells. The best-studied pathway for degranulation is antigen crosslinking of IgE bound to mast-cell Fc IgE receptors, but many other inflammatory stimuli can induce secretion, including complement, direct membrane injury, and certain drugs. Classically, histamine release has been associated with allergy. The contribution of histamine to intraocular inflammation remains subject to debate.
Excerpted from BCSC 2020-2021 series: Section 9 - Uveitis and Ocular Inflammation. For more information and to purchase the entire series, please visit https://www.aao.org/bcsc.